Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes

Epi25  Collaborative,; includes Bahlo, M

Author(s): Epi25 Collaborative,; includes Bahlo, M;
Details: Publication Year 2024-10,Volume 27,Issue #10,Page 1864-1879
Journal Title: Nature Neuroscience
Abstract: Identifying genetic risk factors for highly heterogeneous disorders such as epilepsy remains challenging. Here we present, to our knowledge, the largest whole-exome sequencing study of epilepsy to date, with more than 54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies and generalized and focal epilepsies, whereas most other gene discoveries are subtype specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single-nucleotide/short insertion and deletion variants, copy number variants and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.
Publisher: Springer Nature
Keywords: Humans; *Epilepsy/genetics; *Genetic Predisposition to Disease/genetics; *Exome Sequencing; *Exome/genetics; DNA Copy Number Variations/genetics; Female; Male; Polymorphism, Single Nucleotide/genetics; Risk Factors
Research Division(s): Population Health And Immunity
PubMed ID: 39363051
Publisher's Version: https://doi.org/10.1038/s41593-024-01747-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-25 10:15:29

Last Modified: 2024-10-25 10:15:53